Safety and Plasma Concentrations of a Cyclin-dependent Kinase 9 (CDK9) Inhibitor, FIT039, Administered by a Single Adhesive Skin Patch Applied on Normal Skin and Cutaneous Warts.
Journal
Clinical drug investigation
ISSN: 1179-1918
Titre abrégé: Clin Drug Investig
Pays: New Zealand
ID NLM: 9504817
Informations de publication
Date de publication:
Jan 2019
Jan 2019
Historique:
pubmed:
5
10
2018
medline:
19
3
2019
entrez:
5
10
2018
Statut:
ppublish
Résumé
Cutaneous warts are caused by human papilloma virus (HPV) infection. FIT039, a specific inhibitor of CDK9, suppresses the proliferation of DNA viruses in vitro. We evaluated the safety, plasma concentrations, and efficacy of FIT039 delivered by single application of an adhesive skin patch on normal back skin and cutaneous warts. In this placebo-controlled, dose-escalation, open-label, two-cohort phase I/II clinical trial, after a single administration of a 1% FIT039 patch, 3% FIT039 patch, or placebo on back skin, patients with cutaneous warts were treated with cryotherapy followed by a 1% FIT039 patch for 24 h in the first cohort. In the second cohort, cutaneous warts were treated with cryotherapy followed by a 3% FIT039 patch for 24 h. Adverse events and adverse drug reactions, the concentrations of FIT039, and surface area of cutaneous warts were evaluated. Neither irritant reactions nor symptoms related to FIT039 occurred when the FIT039 patches were applied to patients' backs or on warts in ten patients. The concentrations of FIT039 were under 0.1 ng/ml at every time point. The median wart surface area at 1 week after application of the 1% FIT039 patch was similar to baseline, while that of the 3% FIT039 patch was smaller than baseline. The FIT039 patch showed no topical or systemic adverse reactions when applied on normal skin or cutaneous warts. The safety and good adherence of the FIT039 patch are encouraging and support further studies to evaluate the efficacy of FIT039 in patients with cutaneous warts.
Sections du résumé
BACKGROUND
BACKGROUND
Cutaneous warts are caused by human papilloma virus (HPV) infection. FIT039, a specific inhibitor of CDK9, suppresses the proliferation of DNA viruses in vitro.
PURPOSE
OBJECTIVE
We evaluated the safety, plasma concentrations, and efficacy of FIT039 delivered by single application of an adhesive skin patch on normal back skin and cutaneous warts.
PATIENTS AND METHODS
METHODS
In this placebo-controlled, dose-escalation, open-label, two-cohort phase I/II clinical trial, after a single administration of a 1% FIT039 patch, 3% FIT039 patch, or placebo on back skin, patients with cutaneous warts were treated with cryotherapy followed by a 1% FIT039 patch for 24 h in the first cohort. In the second cohort, cutaneous warts were treated with cryotherapy followed by a 3% FIT039 patch for 24 h. Adverse events and adverse drug reactions, the concentrations of FIT039, and surface area of cutaneous warts were evaluated.
RESULTS
RESULTS
Neither irritant reactions nor symptoms related to FIT039 occurred when the FIT039 patches were applied to patients' backs or on warts in ten patients. The concentrations of FIT039 were under 0.1 ng/ml at every time point. The median wart surface area at 1 week after application of the 1% FIT039 patch was similar to baseline, while that of the 3% FIT039 patch was smaller than baseline.
CONCLUSION
CONCLUSIONS
The FIT039 patch showed no topical or systemic adverse reactions when applied on normal skin or cutaneous warts. The safety and good adherence of the FIT039 patch are encouraging and support further studies to evaluate the efficacy of FIT039 in patients with cutaneous warts.
Identifiants
pubmed: 30284700
doi: 10.1007/s40261-018-0712-7
pii: 10.1007/s40261-018-0712-7
pmc: PMC6510824
doi:
Substances chimiques
Adhesives
0
FIT-039
0
Pyridines
0
CDK9 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 9
EC 2.7.11.22
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
55-61Subventions
Organisme : Japan Agency for Medical Research and Development
ID : Translational Research Network Program
Références
Bruggink SC, de Koning MN, Gussekloo J, Egberts PF, Ter Schegget J, Feltkamp MC, et al. Cutaneous wart-associated HPV types: prevalence and relation with patient characteristics. J Clin Virol. 2012;55(3):250–5.
doi: 10.1016/j.jcv.2012.07.014
pubmed: 22884670
Hagiwara K, Uezato H, Arakaki H, Nonaka S, Nonaka K, Nonaka H, et al. A genotype distribution of human papillomaviruses detected by polymerase chain reaction and direct sequencing analysis in a large sample of common warts in Japan. J Med Virol. 2005;77(1):107–12.
doi: 10.1002/jmv.20421
pubmed: 16032719
Kwok CS, Gibbs S, Bennett C, Holland R, Abbott R. Topical treatments for cutaneous warts. Cochrane Database Syst Rev. 2012;9:CD001781.
Bruggink SC, Gussekloo J, Berger MY, Zaaijer K, Assendelft WJ, de Waal MW, et al. Cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: randomized controlled trial. CMAJ. 2010;182(15):1624–30.
doi: 10.1503/cmaj.092194
pubmed: 20837684
pmcid: 2952009
Meinhart A, Kamenski T, Hoeppner S, Baumli S, Cramer P. A structural perspective of CTD function. Genes Dev. 2005;19(12):1401–15.
doi: 10.1101/gad.1318105
pubmed: 15964991
Okamoto M, Hidaka A, Toyama M, Hosoya T, Yamamoto M, Hagiwara M, et al. Selective inhibition of HIV-1 replication by the CDK9 inhibitor FIT-039. Antiviral Res. 2015;123:1–4.
doi: 10.1016/j.antiviral.2015.08.012
pubmed: 26304705
Tanaka T, Okuyama-Dobashi K, Murakami S, Chen W, Okamoto T, Ueda K, et al. Inhibitory effect of CDK9 inhibitor FIT-039 on hepatitis B virus propagation. Antiviral Res. 2016;133:156–64.
doi: 10.1016/j.antiviral.2016.08.008
pubmed: 27515132
Yamamoto M, Onogi H, Kii I, Yoshida S, Iida K, Sakai H, et al. CDK9 inhibitor FIT-039 prevents replication of multiple DNA viruses. J Clin Invest. 2014;124(8):3479–88.
doi: 10.1172/JCI73805
pubmed: 25003190
pmcid: 4109542
Ajiro M, Sakai H, Onogi H, Yamamoto M, Sumi E, Sawada T, et al. CDK9 inhibitor FIT-039 suppresses viral oncogenes E6 and E7 and has a therapeutic effect on HPV-induced neoplasia. Clin Cancer Res. 2018;24(18):4518–28.
doi: 10.1158/1078-0432.CCR-17-3119
pubmed: 29712686
The International Contact Dermatitis Research Group. http://www.icdrg.org/ . Accessed 15 Jul 2018.
Agency PMDA. Guideline on Bioanalytical Method Validation in Pharmaceutical Development. 2013. https://www.pmda.go.jp/files/000206209.pdf . Accessed 17 Sept 2018.
Oesch F, Fabian E, Guth K, Landsiedel R. Xenobiotic-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models. Arch Toxicol. 2014;88(12):2135–90.
doi: 10.1007/s00204-014-1382-8
pubmed: 25370008
pmcid: 4247477
van Eijl S, Zhu Z, Cupitt J, Gierula M, Gotz C, Fritsche E, et al. Elucidation of xenobiotic metabolism pathways in human skin and human skin models by proteomic profiling. PLoS One. 2012;7(7):e41721.
doi: 10.1371/journal.pone.0041721
pubmed: 22848577
pmcid: 3406074
Sterling JC, Gibbs S, Haque Hussain SS, Mohd Mustapa MF, Handfield-Jones SE. British Association of Dermatologists’ guidelines for the management of cutaneous warts 2014. Br J Dermatol. 2014;171(4):696–712.
doi: 10.1111/bjd.13310
pubmed: 25273231